Molecular Hydrogen Metabolism: a Widespread Trait of Pathogenic Bacteria and Protists

Abstract

SUMMARY Pathogenic microorganisms use various mechanisms to conserve energy in host tissues and environmental reservoirs. One widespread but often overlooked means of energy conservation is through the consumption or production of molecular hydrogen (H2). Here, we comprehensively review the distribution, biochemistry, and physiology of H2 metabolism in pathogens. Over 200 pathogens and pathobionts carry genes for hydrogenases, the enzymes responsible for H2 oxidation and/or production. Furthermore, at least 46 of these species have been experimentally shown to consume or produce H2. Several major human pathogens use the large amounts of H2 produced by colonic microbiota as an energy source for aerobic or anaerobic respiration. This process has been shown to be critical for growth and virulence of the gastrointestinal bacteria Salmonella enterica serovar Typhimurium, Campylobacter jejuni, Campylobacter concisus, and Helicobacter pylori (including carcinogenic strains). H2 oxidation is generally a facultative trait controlled by central regulators in response to energy and oxidant availability. Other bacterial and protist pathogens produce H2 as a diffusible end product of fermentation processes. These include facultative anaerobes such as Escherichia coli, S. Typhimurium, and Giardia intestinalis, which persist by fermentation when limited for respiratory electron acceptors, as well as obligate anaerobes, such as Clostridium perfringens, Clostridioides difficile, and Trichomonas vaginalis, that produce large amounts of H2 during growth. Overall, there is a rich literature on hydrogenases in growth, survival, and virulence in some pathogens. However, we lack a detailed understanding of H2 metabolism in most pathogens, especially obligately anaerobic bacteria, as well as a holistic understanding of gastrointestinal H2 transactions overall. Based on these findings, we also evaluate H2 metabolism as a possible target for drug development or other therapies.

Characterization of a putative sensory [FeFe]-hydrogenase provides new insight into the role of the active site architecture

“…3,4 Phylogenetically, [FeFe]-hydrogenases can be broadly divided into four main groups, denoted group A, B, C, and D, which in turn contain numerous subclasses. [5][6][7][8][9] Considering the wellconserved nature of the auxiliary proteins involved in cofactor assembly (HydEFG), 6 they all arguably share a dependence on the same hexanuclear iron cofactor, the "H-cluster". This biologically unique cofactor consists of a canonical [4Fe-4S] cluster ([4Fe-4S] H ) connected to a low valent dinuclear iron complex ([2Fe] H ).…”

“…It will also serve to strengthen efforts related to biotechnological energy applications and potentially facilitate the development of selective antibiotics. 8,9 We recently reported the whole-cell characterization of an [FeFe]-hydrogenase from the thermophilic rmicute Thermoanaerobacter mathranii in E. coli. 40 The enzyme belongs to the hitherto uncharacterised M2e subclass, which displays a number of well-conserved differences in amino acid sequence as compared to the prototypical group A hydrogenases; namely in the active site cavity and the proton transfer pathway (Fig.…”

“…5 Still, it is phylogenetically most closely related to the M2f subclass of group C, which has been identied as "putative sensory" and includes the recently characterized Tm HydS enzyme from Thermotoga maritima. 5,7,8,38 In addition to the Hdomain, which harbors the H-cluster, both subclasses feature an N-terminal domain with two [4Fe-4S] cluster-binding motifs as well as a C-terminal domain with a four-cysteine motif (Cx 2 -Cx 4 Cx 16 C) indicative of iron-sulfur (FeS) cluster binding. Additionally, the highly conserved cysteine residue initiating the proton transfer pathway from the adt amine in group A [FeFe]hydrogenase is not conserved in the M2e and M2f subclasses (C299, CpI numbering is used throughout the text unless otherwise noted).…”

New Approaches to an Old Problem: Original Techniques in [FeFe]-hydrogenase Research

“…This is also relevant from a medical perspective since many of these organisms are involved in human pathogenesis. 11 Beyond hydrogen turnover activity, the bifurcating, multimeric [FeFe]-hydrogenases of Group A are interesting for the study of catalytic reactions coupled to H2 turnover, e.g. NAD(P)H and CO2 conversion.…”

“…6 Phylogenetically, there are indications that [FeFe]hydrogenases could be the most recent class as archaea rely on [Fe]-and [NiFe]-hydrogenase whereas certain unicellular plants encode for [FeFe]-hydrogenase exclusively. [7][8][9][10][11] All [FeFe]hydrogenases share a biologically unique cofactor, the hydrogen-activating 'H-cluster'. This organometallic moiety consists of a [4Fe-4S] cluster connected to a diiron site via a bridging cysteine (Figure 1).…”